■ The reputation of the shy, retiring Loxosceles reclusa far exceeds the spider's range, confusing efforts to diagnose or accurately track the true incidence of its bite.

Last fall, when a 7-month-old child, admitted to a New York hospital with a swollen arm and a runny sore, developed hemolytic anemia, the working diagnosis was brown recluse spider bite.

But days later, cutaneous anthrax was reported at media offices in the city, and the baby, who had visited the ABC News studio with his mother, tested positive for the bacilli. The infant's severe systemic symptoms were atypical for anthrax, a disease all but unheard of in U.S. population centers for decades.

It was, in other words, an interesting case, and one that drew significant attention in light of the national emergency -- the country's youngest anthrax victim. But in other respects, the case was commonplace.

More than 2,000 brown recluse bites are reported to poison control centers each year. And, if epidemiology and confirmed cases are any indication, most of them are something else.

"Doctors are horrible [about] misdiagnosing any kind of necrotic-looking wounds as brown recluse bites," says Sean P. Bush, MD, a professor of emergency medicine at Loma Linda School of Medicine. An envenomation specialist, he has become the "go-to doctor" in Southern California for suspected spider bites.

In the emergency department "you see a necrotic wound every other shift," he says, but spider bites are a rarity. Even with black widows, which "are totally ubiquitous here," he only sees about half a dozen bites a year. "If it's an 'exciting year,' maybe 10."

And Dr. Bush doesn't see any brown recluse bites.

"There are no populations of brown recluses in California," wrote Richard S. Vetter in the Western Journal of Medicine in November 2000, yet "several hundred cases of 'brown recluse bites' have been reported to me in the past decade."

"The medical community believes the brown recluse is a common constituent of the spider fauna throughout the country," says Vetter, an arachnologist at the University of California, Riverside. He and Dr. Bush co-authored the Annals of Emergency Medicine's May editorial on overdiagnosis of brown recluse bite.

They're not the first to try to correct that impression. In 1983, arachnologist Willis Gertsch, PhD, and toxicologist Findlay Russell, MD, wrote in Toxicon that of some 600 spider bite cases seen at Los Angeles County General Hospital over 10 years, 80% were something else. "Patients came to the hospital as ... 'probably brown recluse,' and the brown recluse is not found within a thousand miles of the hospital," they wrote.

Facts and fictions

The brown recluse, Loxosceles reclusa, inhabits primarily South Central states, from Texas to Tennessee. But bites are reported regularly across the country.

It is a myth, says Vetter, that brown recluses are transported all around the country and "that's how people get bit."

Isolated itinerant individuals could not be responsible for the hundreds of bites reported outside the spider's territorial range every year. Populations of related Loxosceles species exist in Southwest deserts, but virtually all bites are reported from populated areas.

Even in places thick with spiders, real bites are rare.

The shy, retiring recluse is seldom encountered, if it can avoid it. Nocturnal, fragile and easily damaged, it bites when crushed in its retreat, or when someone rolls onto it in a bed it has unwisely started across.

Often the victim is initially unaware of the bite. In part, this reflects a fact of spider biology. Arthropods such as bees use their venom defensively, and it has evolved to induce pain. But spider venom is used to immobilize prey. Creating pain in mammals is an irrelevance.

Few spiders are poisonous to large animals; most cannot even pierce human skin. Of the spiders that can bite people, most are merely a nuisance. But spider venom is remarkably diverse. Several varieties are capable of causing mildly necrotic wounds, referred to as necrotic arachnidism.

The venom of Loxosceles species contains sphingomyelinase D, a wholly unique venom component in the animal kingdom, says Hernan F. Gomez, MD, a University of Michigan researcher in spider bite toxinology. He and his colleagues have developed an immunoassay capable of detecting Loxosceles venom for up to a week after envenomation.

Here's what often happens: People experience pain or tenderness several hours after the bite as SMD starts to trigger tissue damage. This can last up to six months. Most bites are uneventful. A minority develop the dermonecrosis that has made the spider famous.

In these cases, a bluish sinking patch with ragged edges and a surrounding redness appears within 24 to 72 hours, says William V. Stoecker, MD. He described clinical aspects at an arachnidism symposium that Vetter organized as part of June's American Arachnological Society meeting. This is the "red, white and blue sign." Bruising may spread along lymphatics, or with gravity. Often there is a central blister.

But these symptoms overlap with many other dermatologic conditions.

"I don't think it's easy just from the wound itself to say it is brown recluse," especially in nonendemic areas where one would seldom encounter it, said Kevin C. Osterhoudt, MD, a toxicologist at Children's Hospital of Philadelphia.

"Many physicians, when they see a necrotic wound, don't have a broad differential diagnosis for it. And they've been told that brown recluse is what causes wounds like that." At a recent conference of Pennsylvania emergency physicians, he asked how many had seen brown recluse in their ED "and most of them raised their hands."

Show me the spider

Media attention and public dread have made loxoscelism what Dr. Stoecker calls a "disease du jour," and many patients are convinced they have it.

"They get very angry and upset" if contradicted, says Dr. Osterhoudt. Many Web sites, he adds, tell of patients' "recurrent diseases brought on by brown recluse," and how "doctors just won't believe them."

This is exacerbated by poison control data, as centers are dependent on the information provided by callers.

Few patients present with a spider, though. Even a stomped-on specimen has diagnostic value, since specialists rely on the sclerotized genitalia, eye arrangement, and hard-to-squish features like leg spination (absent in Loxosceles), not the highly variable markings, to make their ID.

The paucity of authoritatively confirmed cases has plagued the literature. Researchers have had to use tiny samples and/or rely on presumed or probable cases. This leaves clinicians with a composite picture drawn in part from erroneous best guesses.

With no readily available test, most diagnoses -- and misdiagnoses -- are based on the general look of the wound.

"The most common thing I see misdiagnosed is just a common cellulitis," says Dr. Bush. "In the center of the wound there will be a little necrosis."

Dr. Stoecker, a dermatologist at the University of Missouri Health Sciences Center in Columbia -- the heart of brown recluse country -- offers some rules of thumb: "If you have a big bite, not irregular, no spread -- forget it."

That is more likely a bacterial infection, he says; or pyoderma gangrenosum: "It's big, it's wet. These things ulcerate early. Within three days, you can put a probe 10 cm into the wound." The lesion from a brown recluse bite is usually dry and not as extensive.

For loxoscelism, supportive care is the standard. But many look-alike conditions call for specific treatments: antibiotics for bacterial infections; iodides for sporotrichosis; change of regimen for drug-related outbreaks. False spider bite diagnoses can delay or prevent treatment of serious conditions.

A worst case may be necrotizing fasciitis. "This is a medical and surgical emergency," says Dr. Bush. "You start broad-spectrum antibiotics immediately, and excision. You have to get out in front of it. NF has a huge mortality."

The systemic effects of loxoscelism, such as the hemolysis that complicated the New York anthrax case, are less common and poorly understood. They account for all eight recorded fatalities, most in children. In no case was the bite confirmed. There is no direct relationship with the severity of the wound.

Similarly, the hobo spider, Tegenaria agrestis, sprang to prominence with the 1996 publication of three dramatic cases, including a hemolytic fatality without a confirmed spider bite. Researchers have not yet reproduced the dermonecrosis attributed to the hobo, whose venom chemistry is not as well-known.

Data based on conjectural results have also made it hard to determine efficacy of various treatments. Among them: Dapsone, a sulfone antibiotic used to treat Hansen's disease, to damp neutrophil aggregation; hyberbaric oxygen to alter the venom's chemistry; steroids; electric shock and nitroglycerin patches.

Controlled studies have not yet found any therapy to be effective, although Dr. Stoecker suggests Lidoderm patches for pain. Surgical excision, once standard, is now thought to retard wound healing and to boost the release of serum amyloid protein, augmenting necrosis.

"Pharmacoeconomic obstacles"

In Dr. Gomez's lab, however, a Loxosceles-specific antivenin inhibits the necrotic process in rabbits. Similar to CroFab, the rattlesnake antivenin introduced last year, the experimental antidote uses Fab fragment -- the antigen-binding portion of the antibody -- to inactivate the SMD and minimize the chance of an immune reaction.

Ironically perhaps, notes Dr. Gomez, it is the limited scope of the brown recluse -- that only "maybe 10 of the 50 states" have the spider and "the vast majority [of victims] will do just fine with purely supportive care" -- that makes it unlikely pharmaceutical firms will invest in bringing the antidote to market.

The "pharmacoeconomic obstacles" may not limit his lab's immunoassay, which would not require the same elaborate testing. And indeed, once optimized, it could play a key role in testing an antidote or other proposed treatments, by identifying confirmed cases.

Confirmed cases would change the brown recluse picture, Dr. Gomez says, making evidence-based medicine possible, and dispelling myth -- "because right now, in practical terms, there is no way to identify brown recluse bites."

Differential diagnosis

This annotated list is not an exhaustive compendium of all conditions that have been or could be mistaken for a brown recluse spider bite, but suggest the range of possibilities. Notes include factors to be considered.

Other arthropods Bugs, ticks, fleas, bedbugs, mosquitoes, lice and flies are among the arthropods that seek out humans for a blood meal. Many bites or stings have a boil-like onset, central swelling and redness. Ants, bees and wasps usually produce sharp, immediate pain. Some beetles do not bite but excrete a vesicant. Mites, centipedes and several non-loxoscelid spiders can also produce a necrotic wound.

Cellulitis or impetigo Very common, typically streptococcal infections, often with multiple large blisters and diffuse, spreading, acute inflammation with leukocyte infiltration. Skin is red, hot and edematous. Impetigo tends to have a honey-crusted look. Cellulitis is usually characterized by a hard, red surface, sometimes with a necrotic center. Severe infections are often accompanied by high fever and hypotension, with more pronounced leukocytosis than seen in loxoscelism.

Pyoderma gangrenosum The painful, moist ulcerations have necrotic, bluish-red edges that overhang the lesion. They are large and deep and appear frequently on the legs, with multiple pustules or dark hemorrhagic nodules, often in conjunction with inflammatory bowel disease.

Drug eruption Medications can evoke skin conditions ranging from urticarial allergic reaction to erythema multiforme. Blisters with skin necrosis are induced by warfarin, heparin, halogens (bromoderma) and barbiturates, among others. Onset of ulceration can be abrupt. Heparin necrosis can be superficial, with "connected lakes."

Contact or chemical dermatitis Triggered by allergic reaction (including poison oak, poison ivy and sumac) or chemical irritants, these may mimic a variety of dermatologic conditions. Contact dermatitis is most often itchy, chemical dermatitis more often painful, with fluid-filled blisters, tenderness, redness and swelling.

Diabetic or venous stasis ulcer Venous insufficiency impairs blood return. Changes in skin color and texture develop into a brawny swelling and, in advanced cases, to ulceration surrounded by dry, flaky skin. Often seen on the lower legs or the lateral foot when the underlying cause is diabetes.

Bed sore Advanced decubitus ulcers or pressure ulcers have skin loss over pressure points. Damage or necrosis of subcutaneous tissues that may extend down into underlying fascia, often with a craterlike ulcer. Signs include pus, foul odor, a hot and tender area, and sometimes fever. Patients with dehydration, malnutrition or decreased pain-awareness are at increased risk for pressure ulcers, as are bed- bound patients.

Soft-tissue trauma Delay in seeking treatment for an injury can lead to necrosis. Unexplained physical injuries or bruises of different ages can suggest domestic violence or abuse.

Ecthyma gangrenosum Ulcers associated with serious prolonged neutropenia and/or serious bacterial infection. A painless nodular lesion develops a central hemorrhagic area that gives way to a necrotic ulcer. Often anogenital. Patients often prove to be immunocompromised.

Cutaneous/focal vasculitis Occlusion of blood vessels leading to tissue death. Purpura at onset. Can strongly resemble loxoscelism in the early stage when there is a single lesion, but necrotic ulcers can be considerably more extensive. Infarctive ulcers, often large and necrose due to blood vessel occlusion. Can be seen with rheumatoid arthritis, lupus.

Herpes simplex/varicella zoster A recurrent viral infection with fluid-filled blisters clustered in an inflamed area. Clusters are separated by normal skin and can appear on side only, stopping at the midline. The vesicles eventually rupture and ulcerate; progression can be extremely rapid. Most cases involve the trunk, head and/or face. Herpes simplex can be impetigo-like; varicella zoster often appears in a dermatomal (belt-like) pattern involving only one side of the body.

Lyme disease The second-fastest growing infectious disease in the United States -- spread by ticks endemic in the Northeast, Great Lakes and Pacific Northwest -- Lyme disease is often misdiagnosed. Erythema migrans, an early sign of Lyme disease, starts as a red macule or papule that expands to as much as 50 cm, followed by multiple smaller lesions with hard centers, resulting in a "bull's-eye rash." Also common are fever, fatigue, headache, and pain in muscles or joints. Misdiagnosis can result in permanent neurological or other damage.

Polyarteritis nodosa A necrotizing, segmental vasculitis of muscular arteries with red nodules, ischemia of surrounding tissue and PMN infiltration, usually in men. Often with symptoms such as fever, weakness, headache, abdominal pain and weight loss. About 60% have renal involvement. Cause is unknown. Typically fatal if untreated. A less virulent cutaneous form affects only the skin, muscles and joints.

Sporotrichosis Infection by a plant saprophytic fungus, characterized by nodules, ulcers and abscesses. Often follows punctures from thorns or barbs in those who handle sphagnum moss or other plant material, with symptoms appearing within three weeks of the incident. The initially painless nodules suppurate and produce pus or a bloody discharge. Secondary lesions can appear along lymphatic lines.

Tularemia An acute infectious disease caused by aerobic bacillus, "rabbit fever" or "deer-fly fever" follows exposure to various mammals, including rodents, or blood-sucking arthropods; it has been cited as a possible biological weapon. A primary local ulcerative lesion, sometimes with conjunctivis, regional lymphadenopathy, persistent fever and profound systemic symptoms. Onset is sudden, with chills, fever and body aches. Can persist as a cellulitis-like chronic ulcer.

Chagas' disease American trypanosomiasis, the most common cause of congestive heart failure in the world, is endemic in rural Latin America. It is transmitted by contamination of the bite wound of bloodsucking kissing bugs or other reduviid bugs. "Romana's sign," a painless swelling around one eye, is the classic sign of the acute infection, accompanied by fever, and swelling in the face and lower limbs.

Lymphomatoid papulosis A rare low-grade cutaneous T-cell lymphoma, also called "Macaulay's disease." The recurring, itching papules may ulcerate and then heal spontaneously, leaving depressed oval scars. LyP is estimated to be precursor to or concurrent with more serious malignancies in 10% to 20% of cases.

Anthrax Once called the "malignant pustule," the cutaneous form starts as a dark pustule that grows. Extensive surrounding area shows redness, hardening and vesiculation, sometimes accompanied by lymphoadenopathy. Central ulceration, with a red discharge, is followed by the black scab for which the disease is named. Cutaneous anthrax is painless; similar- appearing lesions that follow spider bites are usually associated with pain.

Necrotizing fasciitis The "flesh-eating bacteria," usually caused by a combination of aerobic and anaerobic bacteria, is characterized by swelling and rapidly progressive necrosis of subcutaneous tissue and fascia. Occlusion of small blood vessels leads to ischemic undermining of surrounding tissue. Therapy hinges on rapid and extensive incision and debridement as well as broad spectrum antibiotic coverage. Mortality is about 30%. Misdiagnosis could result in loss of life or limb.

Source: Recurring items in published differential diagnoses of loxoscelism, with annotations drawn from the clinical literature, augmented with information from the arachnidism symposium, AAS 2002, Riverside.

Spider bytes

A Kansas homeowner working with California arachnologist Richard S. Vetter collected 2,055 brown recluses, by hand and with sticky traps, in her house during six months, while her family lived there; no one was bitten.

Eight Oklahoma 8th graders collected 60 recluses in about seven minutes from loose bricks for a class entomology project -- also without being bitten. That's more than one per child per minute, says Vetter, an indication of the densities found where the spider is established.

Lymphomatoid papulosis is a rare low-grade cutaneous T-cell lymphoma, with papules that sometimes ulcerate. A LyP support group told Vetter that 102 members had, between them, received reportedly 14 diagnoses of spider bites. One member, from a non-endemic area, "had his 'brown recluse bite' surgically removed."

Pennsylvania pediatrician Kevin C. Osterhoudt, MD, has had about 30 spiders mailed to him by families who were sure they'd caught a recluse. "One family was so upset when I said their spider was a [harmless] house spider that they mailed me six or seven more."

In his description of a 9-year-old boy with Lyme disease mimicking loxoscelism, Dr. Osterhoudt notes that the family "brought several pages of medical information regarding the treatment of brown recluse bites, which they had downloaded from the Internet, with them to the ED" and the boy's father "reported chasing a 'brown recluse spider' out of the kitchen."

California emergency physician Sean P. Bush, MD, testified in a case in which the plaintiff contended her landlord's negligence in pest control led to her husband's death. The plaintiff had seen cobwebs in the apartment; doctors diagnosed "brown recluse spider bite," although the location was outside the spider's range. Group A, beta-hemolytic streptococci isolated from the patient's wounds and blood showed death was from complications of necrotizing fasciitis and septic shock. No spiders were found the apartment.

A 1996 report on necrotic arachnidism in the Pacific Northwest in Morbidity and Mortality Weekly Report described a 56-year-old Washington woman who developed severe headache, nausea and altered mentation within 24 hours of "being bitten by a bug." Symptoms persisted but she did not seek help until she began to bleed from her ears and other orifices several weeks later. She died of massive internal hemorrhage. Tegenaria agrestis spiders were subsequently found along a railroad track near her house.

A 52-year-old Michigan man drove home with hunting gear purchased at an Ohio firearms convention heavily attended by Southern gun dealers. Four days later, he sought help for a large necrotic lesion on his leg. Loxosceles venom was detected in a punch biopsy and hairs from the lesion, using enzyme immunoassay developed by University of Michigan toxicologist Hernan F. Gomez, MD, and colleagues. This was the first test of the assay with a human subject.

Brazilians believed that the wolf spider was responsible for necrotic wounds. An antivenin was used for many years until a study of 515 patients who brought in the spider failed to find a single case of necrosis.

In Australia, several recent large series of confirmed bites, as well as laboratory research, produced no evidence that the white-tailed spider can generate the necrotic wounds to which it owes its notoriety.